IgM antibodies play important roles in protection and in adaptive immune responses. Normally, IgM is secreted as pentamers but other forms, including monomers, are sometimes produced. These are prevalent in various diseases, including chronic infections and certain autoimmune diseases. The overall goals of the proposed experiments are to help understand the role that IgM plays in immunity to pathogens and to determine if IgM monomers are beneficial or deleterious to the host. To accomplish this, 1) we will determine the effect of monomeric IgM on primary and secondary immune responses to specific antigens using a transgenic mouse model in which a mutant secretory mu chain (musC575A), which does not polymerize normally, has been expressed. We will determine the consequences, either positive or negative, of the expression of monomeric IgM in the presence and absence of pentameric IgM. 2) We will produce mice in which the endogenous secretory mu gene contains a targeted mutation such that the secretory IgM produced is non-polymeric. These mice will be evaluated for their ability to generate primary and secondary immune responses, and to clear pathogens. The repertoire of natural antibodies with specificities for particular antigens on pathogens will be compared with that of normal and secretory IgM deficient mice. 3) We will determine if the presence of high concentrations of monomeric IgM (also called low molecular weight, LMW IgM) leads to systemic autoimmune disease, either alone or in combination with wildtype IgM or antibodies of other isotypes. We will determine the role of T cells in this process. 4) We will determine if LMW IgM is an accelerator or autoimmune disease in susceptible mice. We will also determine if the presence of genes that predispose toward autoimmunity leads to increased production of LMW IgM. Finally, 5) we will determine if the redox state of B cells is altered in mice undergoing chronic infections, and/or in B cells producing LMW IgM compared with that of normal B cells. We will test the hypothesis that these changes lead to alterations in the quality control standards that regulate IgM assembly and secretion, resulting in the increased production of monomeric IgM. Together, the results of these experiments will provide novel insights into the role of IgM in natural immunity and in disease, and will also shed new light on the pathogenic effects of monomeric IgM.